Lymphoma & Plasma Cell Disorders

Patient receiving chemotherapy

Credit: Rhoda Baer

A new study suggests that half of all people recently diagnosed with cancer in England and Wales should survive their disease for at least 10 years, whereas, 40 years ago, only about a quarter of cancer patients could expect the same.

The research, published in The Lancet, showed significant improvements in long-term cancer survival rates from 1971 to 2011, particularly among patients with hematologic malignancies.

Unfortunately, the outlook for some malignancies remained extremely poor over the period studied.

“Although survival for some cancers has improved dramatically over the past 40 years, others are lagging far behind,” said Manuela Quaresma, of the London School of Hygiene & Tropical Medicine in the UK.

“More investment is urgently needed to improve early diagnosis and provide the best treatment, including more specialist surgeons for poor-prognosis cancers like lung cancer, which have shown little or no evidence of improvement in long-term survival (5 and 10 years after diagnosis) over the past 40 years.”

Quaresma and her colleagues analyzed survival trends for more than 7 million adults (aged 15 to 99 years) diagnosed with one of 21 common cancers in England and Wales between 1971 and 2011, and followed up to the end of 2012.

The researchers observed an increase in 10-year survival for all cancers combined. Twenty-four percent of patients diagnosed in 1971-1972 survived at least 10 years. And 49.8% of patients diagnosed in 2010-2011 are expected to survive at least 10 years.

The data revealed substantial improvements for patients with hematologic malignancies as well. For Hodgkin lymphoma, the 10-year survival rate rose from 47.7% for patients diagnosed in 1971-1972 to 80% for those diagnosed in 2010-2011.

For non-Hodgkin lymphoma, the 10-year survival rate increased from 22% to 63.1%. For multiple myeloma, it rose from 6.2% to 32.6%. And for leukemia, it rose from 6.9% to 46.1%.

The researchers noted that the most recent 10-year survival estimates are above 70% for cancers of the breast, prostate, testis, and uterus, as well as for melanoma and Hodgkin lymphoma. Furthermore, improvements in survival are greatest for these cancers.

Unfortunately, several other malignancies continue to have poor long-term survival. For cancers of the brain, stomach, lung, esophagus, and pancreas, 10-year survival after diagnosis is still below 15% for patients diagnosed in 2010-2011.

“These 5 cancers impose a huge public health burden, both because they are common and because they are often diagnosed at a late stage, when they are much harder to treat,” said study author Bernard Rachet, MD, PhD, of the London School of Hygiene & Tropical Medicine.

Dr Rachet also noted that this research confirms a persistent “age gap” in survival between younger and older patients for all cancers.

“Even after we have adjusted for the fact that older people have much higher death rates from other diseases than younger people, elderly cancer patients are doing worse for all cancers,” he said.

“This problem is particularly marked in the UK. In other countries, the age gap in cancer survival has become much narrower over the last 15 to 20 years than in England and Wales.”

Patient receiving chemotherapy

Credit: Rhoda Baer

A new study suggests that half of all people recently diagnosed with cancer in England and Wales should survive their disease for at least 10 years, whereas, 40 years ago, only about a quarter of cancer patients could expect the same.

The research, published in The Lancet, showed significant improvements in long-term cancer survival rates from 1971 to 2011, particularly among patients with hematologic malignancies.

Unfortunately, the outlook for some malignancies remained extremely poor over the period studied.

“Although survival for some cancers has improved dramatically over the past 40 years, others are lagging far behind,” said Manuela Quaresma, of the London School of Hygiene & Tropical Medicine in the UK.

“More investment is urgently needed to improve early diagnosis and provide the best treatment, including more specialist surgeons for poor-prognosis cancers like lung cancer, which have shown little or no evidence of improvement in long-term survival (5 and 10 years after diagnosis) over the past 40 years.”

Quaresma and her colleagues analyzed survival trends for more than 7 million adults (aged 15 to 99 years) diagnosed with one of 21 common cancers in England and Wales between 1971 and 2011, and followed up to the end of 2012.

The researchers observed an increase in 10-year survival for all cancers combined. Twenty-four percent of patients diagnosed in 1971-1972 survived at least 10 years. And 49.8% of patients diagnosed in 2010-2011 are expected to survive at least 10 years.

The data revealed substantial improvements for patients with hematologic malignancies as well. For Hodgkin lymphoma, the 10-year survival rate rose from 47.7% for patients diagnosed in 1971-1972 to 80% for those diagnosed in 2010-2011.

For non-Hodgkin lymphoma, the 10-year survival rate increased from 22% to 63.1%. For multiple myeloma, it rose from 6.2% to 32.6%. And for leukemia, it rose from 6.9% to 46.1%.

The researchers noted that the most recent 10-year survival estimates are above 70% for cancers of the breast, prostate, testis, and uterus, as well as for melanoma and Hodgkin lymphoma. Furthermore, improvements in survival are greatest for these cancers.

Unfortunately, several other malignancies continue to have poor long-term survival. For cancers of the brain, stomach, lung, esophagus, and pancreas, 10-year survival after diagnosis is still below 15% for patients diagnosed in 2010-2011.

“These 5 cancers impose a huge public health burden, both because they are common and because they are often diagnosed at a late stage, when they are much harder to treat,” said study author Bernard Rachet, MD, PhD, of the London School of Hygiene & Tropical Medicine.

Dr Rachet also noted that this research confirms a persistent “age gap” in survival between younger and older patients for all cancers.

“Even after we have adjusted for the fact that older people have much higher death rates from other diseases than younger people, elderly cancer patients are doing worse for all cancers,” he said.

“This problem is particularly marked in the UK. In other countries, the age gap in cancer survival has become much narrower over the last 15 to 20 years than in England and Wales.”

Patient receiving chemotherapy

Credit: Rhoda Baer

A new study suggests that half of all people recently diagnosed with cancer in England and Wales should survive their disease for at least 10 years, whereas, 40 years ago, only about a quarter of cancer patients could expect the same.

The research, published in The Lancet, showed significant improvements in long-term cancer survival rates from 1971 to 2011, particularly among patients with hematologic malignancies.

Unfortunately, the outlook for some malignancies remained extremely poor over the period studied.

“Although survival for some cancers has improved dramatically over the past 40 years, others are lagging far behind,” said Manuela Quaresma, of the London School of Hygiene & Tropical Medicine in the UK.

“More investment is urgently needed to improve early diagnosis and provide the best treatment, including more specialist surgeons for poor-prognosis cancers like lung cancer, which have shown little or no evidence of improvement in long-term survival (5 and 10 years after diagnosis) over the past 40 years.”

Quaresma and her colleagues analyzed survival trends for more than 7 million adults (aged 15 to 99 years) diagnosed with one of 21 common cancers in England and Wales between 1971 and 2011, and followed up to the end of 2012.

The researchers observed an increase in 10-year survival for all cancers combined. Twenty-four percent of patients diagnosed in 1971-1972 survived at least 10 years. And 49.8% of patients diagnosed in 2010-2011 are expected to survive at least 10 years.

The data revealed substantial improvements for patients with hematologic malignancies as well. For Hodgkin lymphoma, the 10-year survival rate rose from 47.7% for patients diagnosed in 1971-1972 to 80% for those diagnosed in 2010-2011.

For non-Hodgkin lymphoma, the 10-year survival rate increased from 22% to 63.1%. For multiple myeloma, it rose from 6.2% to 32.6%. And for leukemia, it rose from 6.9% to 46.1%.

The researchers noted that the most recent 10-year survival estimates are above 70% for cancers of the breast, prostate, testis, and uterus, as well as for melanoma and Hodgkin lymphoma. Furthermore, improvements in survival are greatest for these cancers.

Unfortunately, several other malignancies continue to have poor long-term survival. For cancers of the brain, stomach, lung, esophagus, and pancreas, 10-year survival after diagnosis is still below 15% for patients diagnosed in 2010-2011.

“These 5 cancers impose a huge public health burden, both because they are common and because they are often diagnosed at a late stage, when they are much harder to treat,” said study author Bernard Rachet, MD, PhD, of the London School of Hygiene & Tropical Medicine.

Dr Rachet also noted that this research confirms a persistent “age gap” in survival between younger and older patients for all cancers.

“Even after we have adjusted for the fact that older people have much higher death rates from other diseases than younger people, elderly cancer patients are doing worse for all cancers,” he said.

“This problem is particularly marked in the UK. In other countries, the age gap in cancer survival has become much narrower over the last 15 to 20 years than in England and Wales.”

 

 

CLL cells

 

The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.

Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.

Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.

Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.

At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m².

Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

 

 

CLL cells

 

The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.

Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.

Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.

Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.

At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m².

Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

 

 

CLL cells

 

The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.

Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.

Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.

Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.

At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m².

Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

Blood samples

Credit: Graham Colm

Two teams of researchers have identified somatic mutations that increase the likelihood a person will develop a hematologic malignancy.

This “pre-malignant” stage was detected simply by sequencing DNA from blood samples.

The researchers found that subjects carrying certain mutations had more than 10 times the risk of developing a hematologic malignancy than individuals without the mutations. And the risk increased with age.

Steven McCarroll, PhD, of Harvard Medical School in Boston, Massachusetts, and Benjamin Ebert, MD, PhD, also of Harvard Medical School, reported these findings in NEJM.

Both research teams looked at somatic mutations in DNA samples collected from the blood of subjects who had not been diagnosed with cancer or blood disorders.

Taking two very different approaches, the teams found that a surprising percentage of individuals had acquired a subset of the somatic mutations present in hematologic malignancies. And subjects with the mutations were more likely to develop these cancers.

This pre-malignant state was rare in individuals under the age of 40. But it appeared with increasing frequency with each decade of life, ultimately appearing in more than 10% of individuals over the age of 70.

The researchers believe these early mutations lie in wait for follow-on, cooperating mutations that, when they occur in the same cells as the earlier mutations, drive the cells toward cancer. The majority of mutations occurred in just 3 genes: DNMT3A, TET2, and ASXL1.

Dr Ebert’s group

Dr Ebert and his colleagues had hypothesized that, since hematologic malignancies increase with age, it might be possible to detect early somatic mutations that could be initiating the disease process, and these mutations might increase with age.

The researchers looked specifically at 160 genes known to be recurrently mutated in hematologic malignancies, using genetic data derived from approximately 17,000 blood samples originally obtained for studies on the genetics of type 2 diabetes.

The team found a roughly 11-fold increase in the risk of hematologic malignancy among subjects with the subset of somatic mutations linked to blood cancers. And there was a clear association between age and the frequency of these mutations.

Men were slightly more likely to have the mutations than women, and Hispanics were slightly less likely to have the mutations than other racial/ethnic groups.

The researchers also found an association between the presence of this pre-malignant state and the risk of overall mortality independent of malignancy. Individuals with the mutations had a higher risk of type 2 diabetes, coronary heart disease, and ischemic stroke as well.

However, additional research will be needed to determine the nature of these associations.

Dr McCarroll’s group

Dr McCarroll and his colleagues discovered the same phenomenon while trying to determine whether somatic mutations contribute to the risk of developing schizophrenia.

The team studied roughly 12,000 DNA samples from patients with schizophrenia and bipolar disorder, as well as healthy controls, searching across the whole genome at all of the protein-coding genes for patterns in somatic mutations.

The somatic mutations were concentrated in a handful of genes that turned out to be cancer genes.

So the researchers used electronic medical records to follow the patients’ medical histories, finding that subjects with these acquired mutations had a nearly 13-fold higher risk of developing a hematologic malignancy than subjects without the mutations.

The team conducted follow-up analyses on tumor samples from 2 patients who had progressed from this pre-malignant state to cancer. In both cases, the cancer developed from the same cells that had harbored the initiating mutations years earlier.

“The fact that both teams converged on strikingly similar findings, using very different approaches and looking at DNA from very different sets of patients, has given us great confidence in the results,” said study author Giulio Genovese, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

Next steps

The researchers emphasized that there is no clinical benefit today for testing for this pre-malignant state, as there are no treatments currently available that would address this condition in otherwise healthy people.

However, they said the results open the door to entirely new directions for research, toward early detection and even prevention of hematologic malignancies.

“The results demonstrate a way to identify high-risk cohorts—people who are at much higher than average risk of progressing to cancer—which could be a population for clinical trials of future prevention strategies,” Dr McCarroll said. “The abundance of these mutated cells could also serve as a biomarker—like LDL cholesterol is for cardiovascular disease—to test the effects of potential prevention therapies in clinical trials.”

Dr Ebert added, “A new focus of investigation will now be to develop interventions that might decrease the likelihood that individuals with these mutations will go on to develop overt malignancies, or therapeutic strategies to decrease mortality from other conditions that may be instigated by these mutations.”

This research is set to be presented on December 9 at the 56th ASH Annual Meeting in San Francisco.

Blood samples

Credit: Graham Colm

Two teams of researchers have identified somatic mutations that increase the likelihood a person will develop a hematologic malignancy.

This “pre-malignant” stage was detected simply by sequencing DNA from blood samples.

The researchers found that subjects carrying certain mutations had more than 10 times the risk of developing a hematologic malignancy than individuals without the mutations. And the risk increased with age.

Steven McCarroll, PhD, of Harvard Medical School in Boston, Massachusetts, and Benjamin Ebert, MD, PhD, also of Harvard Medical School, reported these findings in NEJM.

Both research teams looked at somatic mutations in DNA samples collected from the blood of subjects who had not been diagnosed with cancer or blood disorders.

Taking two very different approaches, the teams found that a surprising percentage of individuals had acquired a subset of the somatic mutations present in hematologic malignancies. And subjects with the mutations were more likely to develop these cancers.

This pre-malignant state was rare in individuals under the age of 40. But it appeared with increasing frequency with each decade of life, ultimately appearing in more than 10% of individuals over the age of 70.

The researchers believe these early mutations lie in wait for follow-on, cooperating mutations that, when they occur in the same cells as the earlier mutations, drive the cells toward cancer. The majority of mutations occurred in just 3 genes: DNMT3A, TET2, and ASXL1.

Dr Ebert’s group

Dr Ebert and his colleagues had hypothesized that, since hematologic malignancies increase with age, it might be possible to detect early somatic mutations that could be initiating the disease process, and these mutations might increase with age.

The researchers looked specifically at 160 genes known to be recurrently mutated in hematologic malignancies, using genetic data derived from approximately 17,000 blood samples originally obtained for studies on the genetics of type 2 diabetes.

The team found a roughly 11-fold increase in the risk of hematologic malignancy among subjects with the subset of somatic mutations linked to blood cancers. And there was a clear association between age and the frequency of these mutations.

Men were slightly more likely to have the mutations than women, and Hispanics were slightly less likely to have the mutations than other racial/ethnic groups.

The researchers also found an association between the presence of this pre-malignant state and the risk of overall mortality independent of malignancy. Individuals with the mutations had a higher risk of type 2 diabetes, coronary heart disease, and ischemic stroke as well.

However, additional research will be needed to determine the nature of these associations.

Dr McCarroll’s group

Dr McCarroll and his colleagues discovered the same phenomenon while trying to determine whether somatic mutations contribute to the risk of developing schizophrenia.

The team studied roughly 12,000 DNA samples from patients with schizophrenia and bipolar disorder, as well as healthy controls, searching across the whole genome at all of the protein-coding genes for patterns in somatic mutations.

The somatic mutations were concentrated in a handful of genes that turned out to be cancer genes.

So the researchers used electronic medical records to follow the patients’ medical histories, finding that subjects with these acquired mutations had a nearly 13-fold higher risk of developing a hematologic malignancy than subjects without the mutations.

The team conducted follow-up analyses on tumor samples from 2 patients who had progressed from this pre-malignant state to cancer. In both cases, the cancer developed from the same cells that had harbored the initiating mutations years earlier.

“The fact that both teams converged on strikingly similar findings, using very different approaches and looking at DNA from very different sets of patients, has given us great confidence in the results,” said study author Giulio Genovese, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

Next steps

The researchers emphasized that there is no clinical benefit today for testing for this pre-malignant state, as there are no treatments currently available that would address this condition in otherwise healthy people.

However, they said the results open the door to entirely new directions for research, toward early detection and even prevention of hematologic malignancies.

“The results demonstrate a way to identify high-risk cohorts—people who are at much higher than average risk of progressing to cancer—which could be a population for clinical trials of future prevention strategies,” Dr McCarroll said. “The abundance of these mutated cells could also serve as a biomarker—like LDL cholesterol is for cardiovascular disease—to test the effects of potential prevention therapies in clinical trials.”

Dr Ebert added, “A new focus of investigation will now be to develop interventions that might decrease the likelihood that individuals with these mutations will go on to develop overt malignancies, or therapeutic strategies to decrease mortality from other conditions that may be instigated by these mutations.”

This research is set to be presented on December 9 at the 56th ASH Annual Meeting in San Francisco.

Blood samples

Credit: Graham Colm

Two teams of researchers have identified somatic mutations that increase the likelihood a person will develop a hematologic malignancy.

This “pre-malignant” stage was detected simply by sequencing DNA from blood samples.

The researchers found that subjects carrying certain mutations had more than 10 times the risk of developing a hematologic malignancy than individuals without the mutations. And the risk increased with age.

Steven McCarroll, PhD, of Harvard Medical School in Boston, Massachusetts, and Benjamin Ebert, MD, PhD, also of Harvard Medical School, reported these findings in NEJM.

Both research teams looked at somatic mutations in DNA samples collected from the blood of subjects who had not been diagnosed with cancer or blood disorders.

Taking two very different approaches, the teams found that a surprising percentage of individuals had acquired a subset of the somatic mutations present in hematologic malignancies. And subjects with the mutations were more likely to develop these cancers.

This pre-malignant state was rare in individuals under the age of 40. But it appeared with increasing frequency with each decade of life, ultimately appearing in more than 10% of individuals over the age of 70.

The researchers believe these early mutations lie in wait for follow-on, cooperating mutations that, when they occur in the same cells as the earlier mutations, drive the cells toward cancer. The majority of mutations occurred in just 3 genes: DNMT3A, TET2, and ASXL1.

Dr Ebert’s group

Dr Ebert and his colleagues had hypothesized that, since hematologic malignancies increase with age, it might be possible to detect early somatic mutations that could be initiating the disease process, and these mutations might increase with age.

The researchers looked specifically at 160 genes known to be recurrently mutated in hematologic malignancies, using genetic data derived from approximately 17,000 blood samples originally obtained for studies on the genetics of type 2 diabetes.

The team found a roughly 11-fold increase in the risk of hematologic malignancy among subjects with the subset of somatic mutations linked to blood cancers. And there was a clear association between age and the frequency of these mutations.

Men were slightly more likely to have the mutations than women, and Hispanics were slightly less likely to have the mutations than other racial/ethnic groups.

The researchers also found an association between the presence of this pre-malignant state and the risk of overall mortality independent of malignancy. Individuals with the mutations had a higher risk of type 2 diabetes, coronary heart disease, and ischemic stroke as well.

However, additional research will be needed to determine the nature of these associations.

Dr McCarroll’s group

Dr McCarroll and his colleagues discovered the same phenomenon while trying to determine whether somatic mutations contribute to the risk of developing schizophrenia.

The team studied roughly 12,000 DNA samples from patients with schizophrenia and bipolar disorder, as well as healthy controls, searching across the whole genome at all of the protein-coding genes for patterns in somatic mutations.

The somatic mutations were concentrated in a handful of genes that turned out to be cancer genes.

So the researchers used electronic medical records to follow the patients’ medical histories, finding that subjects with these acquired mutations had a nearly 13-fold higher risk of developing a hematologic malignancy than subjects without the mutations.

The team conducted follow-up analyses on tumor samples from 2 patients who had progressed from this pre-malignant state to cancer. In both cases, the cancer developed from the same cells that had harbored the initiating mutations years earlier.

“The fact that both teams converged on strikingly similar findings, using very different approaches and looking at DNA from very different sets of patients, has given us great confidence in the results,” said study author Giulio Genovese, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Massachusetts.

Next steps

The researchers emphasized that there is no clinical benefit today for testing for this pre-malignant state, as there are no treatments currently available that would address this condition in otherwise healthy people.

However, they said the results open the door to entirely new directions for research, toward early detection and even prevention of hematologic malignancies.

“The results demonstrate a way to identify high-risk cohorts—people who are at much higher than average risk of progressing to cancer—which could be a population for clinical trials of future prevention strategies,” Dr McCarroll said. “The abundance of these mutated cells could also serve as a biomarker—like LDL cholesterol is for cardiovascular disease—to test the effects of potential prevention therapies in clinical trials.”

Dr Ebert added, “A new focus of investigation will now be to develop interventions that might decrease the likelihood that individuals with these mutations will go on to develop overt malignancies, or therapeutic strategies to decrease mortality from other conditions that may be instigated by these mutations.”

This research is set to be presented on December 9 at the 56th ASH Annual Meeting in San Francisco.

Prescription drugs
Credit: CDC

Swissmedic, the regulatory authority for Switzerland, has granted

approval for lenalidomide (Revlimid) to treat patients with

relapsed or refractory mantle cell lymphoma (MCL) after prior therapy

that included bortezomib and chemotherapy or rituximab.

This is the third approval of lenalidomide for MCL worldwide. The drug is also approved for this indication in the US and Israel.

Swissmedic’s decision to approve the drug was based on results of the phase 2 EMERGE study (MCL-001).

In this trial, researchers evaluated lenalidomide (25 mg once a day on days 1-21 of each 28-day cycle) in 134 MCL patients who had received prior treatment with rituximab, cyclophosphamide, an anthracycline (or mitoxantrone), and bortezomib alone or in combination.

The overall response rate (the primary endpoint) was 28% (37/134), and the complete response rate was 7% (10/134). The median duration of response was 16.6 months (95% CI, 7.7-26.7).

The most common grade 3/4 adverse events reported in at least 5% of patients were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), fatigue (7%), leukopenia (7%), febrile neutropenia (6%), diarrhea (6%), and dyspnea (6%).

“MCL is a rare B-cell lymphoma of the elderly that usually responds quite well to first-line treatment,” said Christoph Renner, MD, of Onkozentrum Hirslanden Zürich.

“However, even intensive treatment does not prevent relapse in the majority of patients, and new therapeutic options are needed. Therefore, having access to lenalidomide, an immunomodulatory drug with a well-known safety profile, will definitely enrich our therapeutic armamentarium.”

Lenalidomide is already approved in Switzerland for use in combination

with dexamethasone to treat patients with multiple myeloma who have

received at least one previous treatment.

The drug is also

approved to treat patients with transfusion-dependent anemia due to low-

or intermediate-risk-1 myelodysplastic syndrome associated with a 5q

deletion, with or without additional cytogenetic abnormalities.

Lenalidomide is under development by Celgene International Sàrl, a wholly owned subsidiary of Celgene Corporation.

Prescription drugs
Credit: CDC

Swissmedic, the regulatory authority for Switzerland, has granted

approval for lenalidomide (Revlimid) to treat patients with

relapsed or refractory mantle cell lymphoma (MCL) after prior therapy

that included bortezomib and chemotherapy or rituximab.

This is the third approval of lenalidomide for MCL worldwide. The drug is also approved for this indication in the US and Israel.

Swissmedic’s decision to approve the drug was based on results of the phase 2 EMERGE study (MCL-001).

In this trial, researchers evaluated lenalidomide (25 mg once a day on days 1-21 of each 28-day cycle) in 134 MCL patients who had received prior treatment with rituximab, cyclophosphamide, an anthracycline (or mitoxantrone), and bortezomib alone or in combination.

The overall response rate (the primary endpoint) was 28% (37/134), and the complete response rate was 7% (10/134). The median duration of response was 16.6 months (95% CI, 7.7-26.7).

The most common grade 3/4 adverse events reported in at least 5% of patients were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), fatigue (7%), leukopenia (7%), febrile neutropenia (6%), diarrhea (6%), and dyspnea (6%).

“MCL is a rare B-cell lymphoma of the elderly that usually responds quite well to first-line treatment,” said Christoph Renner, MD, of Onkozentrum Hirslanden Zürich.

“However, even intensive treatment does not prevent relapse in the majority of patients, and new therapeutic options are needed. Therefore, having access to lenalidomide, an immunomodulatory drug with a well-known safety profile, will definitely enrich our therapeutic armamentarium.”

Lenalidomide is already approved in Switzerland for use in combination

with dexamethasone to treat patients with multiple myeloma who have

received at least one previous treatment.

The drug is also

approved to treat patients with transfusion-dependent anemia due to low-

or intermediate-risk-1 myelodysplastic syndrome associated with a 5q

deletion, with or without additional cytogenetic abnormalities.

Lenalidomide is under development by Celgene International Sàrl, a wholly owned subsidiary of Celgene Corporation.

Prescription drugs
Credit: CDC

Swissmedic, the regulatory authority for Switzerland, has granted

approval for lenalidomide (Revlimid) to treat patients with

relapsed or refractory mantle cell lymphoma (MCL) after prior therapy

that included bortezomib and chemotherapy or rituximab.

This is the third approval of lenalidomide for MCL worldwide. The drug is also approved for this indication in the US and Israel.

Swissmedic’s decision to approve the drug was based on results of the phase 2 EMERGE study (MCL-001).

In this trial, researchers evaluated lenalidomide (25 mg once a day on days 1-21 of each 28-day cycle) in 134 MCL patients who had received prior treatment with rituximab, cyclophosphamide, an anthracycline (or mitoxantrone), and bortezomib alone or in combination.

The overall response rate (the primary endpoint) was 28% (37/134), and the complete response rate was 7% (10/134). The median duration of response was 16.6 months (95% CI, 7.7-26.7).

The most common grade 3/4 adverse events reported in at least 5% of patients were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), fatigue (7%), leukopenia (7%), febrile neutropenia (6%), diarrhea (6%), and dyspnea (6%).

“MCL is a rare B-cell lymphoma of the elderly that usually responds quite well to first-line treatment,” said Christoph Renner, MD, of Onkozentrum Hirslanden Zürich.

“However, even intensive treatment does not prevent relapse in the majority of patients, and new therapeutic options are needed. Therefore, having access to lenalidomide, an immunomodulatory drug with a well-known safety profile, will definitely enrich our therapeutic armamentarium.”

Lenalidomide is already approved in Switzerland for use in combination

with dexamethasone to treat patients with multiple myeloma who have

received at least one previous treatment.

The drug is also

approved to treat patients with transfusion-dependent anemia due to low-

or intermediate-risk-1 myelodysplastic syndrome associated with a 5q

deletion, with or without additional cytogenetic abnormalities.

Lenalidomide is under development by Celgene International Sàrl, a wholly owned subsidiary of Celgene Corporation.

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Hookahs in a shop

Credit: Steven Damron

A new study indicates that individuals exposed to hookah smoke have an increase in the uptake of benzene, a substance linked to the development of hematologic malignancies.

Levels of S-phenylmercapturic acid (SPMA), a metabolite of benzene, were more than 4 times higher after study subjects smoked a hookah than before they did.

And non-smoking subjects experienced a nearly 3-fold increase in SPMA levels after they visited a hookah lounge.

Nada Kassem, RN, DrPH, of San Diego State University in California, and her colleagues reported these findings in Cancer Epidemiology, Biomarkers & Prevention.

“Hookah smoking involves the use of burning charcoal that is needed to heat the hookah tobacco to generate the smoke that the smoker inhales,” Dr Kassem explained.

“In addition to inhaling toxicants and carcinogens found in the hookah tobacco smoke, hookah smokers and non-smokers who socialize with hookah smokers also inhale large quantities of charcoal combustion-generated toxic and carcinogenic emissions.”

To gain more insight into the dangers of hookah smoke, Dr Kassem and her colleagues analyzed levels of SPMA in the urine of 105 hookah smokers and 103 non-smokers.

The team obtained urine samples the morning of and the morning after participants attended a hookah-only smoking event at a hookah lounge or a private home.

SPMA levels in hookah smokers increased 4.2-fold after smoking at a hookah lounge (P<0.001) and increased 1.9-fold after smoking in a private home (P=0.003).

Non-smokers’ SPMA levels increased 2.6-fold after attending a social event in a hookah lounge (P=0.055).

However, non-smokers had similarly high levels of SPMA before and after attending hookah events in a private home (P=0.933). This suggests these subjects had chronic exposure to benzene before the study, according to Dr Kassem.

Regardless, she and her colleagues said the study’s results suggest hookah smoke increases the uptake of benzene, which has been linked to a range of hematologic malignancies, particularly acute myeloid leukemia.

“In contrast to what is believed, hookah tobacco smoking is not a safe alternative to smoking other forms of tobacco,” Dr Kassem said.

She and her colleagues noted that there is no safe level of exposure to benzene. And this suggests a need for interventions to reduce or prevent the use of hookahs, limit hookah-related exposure to toxic substances, and include hookah smoking in clean indoor air legislation.

Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

Frederick Roth, PhD

Credit: Mount Sinai Hospital

Researchers say they’ve created the largest-scale map of direct interactions between proteins encoded by the human genome, and this has revealed dozens of genes that may be involved in cancers.

This human interactome map describes about 14,000 direct interactions between proteins.

The map is about 30% larger than previous maps and contains more high-quality interactions than have come from all previous studies combined, according to the researchers.

Frederick Roth, PhD, of the University of Toronto and Mount Sinai Hospital in Ontario, Canada, and his colleagues described their map in Cell.

First, the researchers identified protein interactions via lab experiments. Then, they used computer modelling to zoom in on proteins that connect to one or more other cancer proteins.

“We show, really for the first time, that cancer proteins are more likely to interconnect with one another than they are to connect to randomly chosen non-cancer proteins,” Dr Roth said.

“Once you see that proteins associated to the same disease are more likely to connect to each other, now you can use this network of interactions as a prediction tool to find new cancer proteins and the genes they encode.”

For example, two known cancer genes encoded two proteins that interacted with CTBP2, a protein encoded at a location tied to prostate cancer, which can spread to nearby lymph nodes. These two proteins are implicated in lymphoid tumors, suggesting that CTBP2 plays a role in the development of lymphoid tumors.

Using their predictive method, the researchers found that 60 of their predicted cancer genes fit into a known cancer pathway.

The study also revealed that the network of protein interactions in humans covers a much broader range of genes than some past research has suggested.

Dr Roth said studies often focus on “popular” proteins that have already been linked to disease or are interesting for other reasons, and this has created a bias in our understanding of protein interactions.

“One major conclusion of the paper is that when you look systematically for interactions, you find them everywhere,” he said.

He and his colleagues believe that knowledge of protein interactions is likely to inform worldwide efforts to sequence and interpret cancer genomes.

Diffuse large B-cell lymphoma

BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.

In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.

And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.

The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.

“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.

The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.

The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.

All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.

E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).

‘Encouraging activity’

Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.

Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.

Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.

Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.

The patient with marginal zone lymphoma achieved stable disease and remains on study.

Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.

“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.

“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”

‘Little toxicity’

All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.

The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.

There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.

“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”

E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.

Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.

Diffuse large B-cell lymphoma

BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.

In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.

And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.

The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.

“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.

The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.

The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.

All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.

E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).

‘Encouraging activity’

Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.

Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.

Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.

Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.

The patient with marginal zone lymphoma achieved stable disease and remains on study.

Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.

“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.

“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”

‘Little toxicity’

All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.

The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.

There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.

“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”

E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.

Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.

Diffuse large B-cell lymphoma

BARCELONA—A small molecule inhibitor of EZH2 has shown “encouraging” activity in patients with advanced non-Hodgkin lymphoma (NHL), according to researchers.

In a phase 1 study, 4 of 10 heavily pretreated NHL patients responded to the drug, E7438 (also known as EPZ6438), with 1 patient achieving a complete response.

And E7438’s activity was not dependent upon the presence of an EZH2 mutation, as all 4 patients had wild-type EZH2.

The drug also demonstrated activity in a patient with a malignant rhabdoid tumor in the brain.

“In this study, responses were seen in patients with lymphoma who were refractory to, or relapsed after, prior standard treatments, as well as in a patient with a malignant disease for which there is no available standard medical treatment [rhabdoid tumor in the brain],” said study investigator Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

Dr Ribrag and his colleagues also found E7438 to be well-tolerated. There were no grade 3 adverse events and only 1 grade 4 event at the maximum dose level.

The researchers presented these data at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics as abstract LBA6. Investigators from Esai and Epizyme, the companies developing E7438, were involved in this trial.

The study included 24 patients who ranged in age from 24 to 84. Twelve patients had solid tumor malignancies, and 12 had NHL. Six patients had diffuse large B-cell lymphoma (DLBCL), 5 had follicular lymphoma (FL), and 1 had marginal zone lymphoma.

All of the patients were heavily pretreated. Fourteen had received between 2 and 4 prior therapies, and 9 had received more than 4 prior treatments.

E7438 was given in 5 dosing cohorts: 100 mg BID (n=6), 200 mg BID (n=3), 400 mg BID (n=3), 800 mg BID (n=6), and 1600 mg BID (n=6).

‘Encouraging activity’

Twenty patients were evaluable for efficacy as of October 20. Among the 10 patients with solid tumor malignancies, 1 responded. The patient with an INI1-deficient malignant rhabdoid tumor achieved a partial response and remains on study.

Four of the 10 evaluable NHL patients achieved a partial response or better, including 1 complete response. Responses were seen across a range of doses, up to the 800 mg BID dose.

Among the 5 evaluable DLBCL patients, 3 achieved a partial response or better. One patient with a partial response subsequently evolved to a complete response upon continued treatment and remains on study at 41 weeks of treatment. One of the 2 patients who achieved a partial response remains on study.

Among the 4 evaluable patients with FL, 1 achieved a partial response and remains on study. Three FL patients achieved stable disease, and 2 of these patients remain on study.

The patient with marginal zone lymphoma achieved stable disease and remains on study.

Confirmatory sequencing in a central lab showed that all 10 NHL patients who were evaluable for efficacy had wild-type EZH2, and responses were observed in both germinal center and non-germinal center lymphoma.

“These results provide encouraging evidence of antitumor activity with [E7438] . . . , including the potential for responses to improve with continued treatment,” said Peter Ho, MD, PhD, chief development officer at Epizyme.

“Given the clinical activity we saw in both wild-type EZH2 and non-germinal center lymphoma patients, our plan for the first phase 2 NHL study is to evaluate EPZ-6438 in DLBCL and FL patients with and without EZH2 mutations.”

‘Little toxicity’

All 24 patients were evaluable for safety and tolerability. The majority of adverse events were grade 1 or 2. Events occurring in more than 10% of patients included asthenia, decreased appetite, and nausea.

The only grade 3/4 treatment-related adverse event was grade 4 thrombocytopenia in 1 patient who received the drug at 1600 mg, which met the criteria for a dose-limiting toxicity.

There were no adverse events that required treatment withdrawal or dose reduction. However, 3 events resulted in dose interruption.

“The maximum tolerated dose was not reached because there was little toxicity observed,” Dr Ribrag said. “Since we saw that the drug was active at doses lower than the maximum dose of 1600 mg twice a day, the dose used for the phase 2 trials planned for 2015 may be lower.”

E7438 was rapidly absorbed and eliminated, with a terminal half-life of 3 to 6 hours. In addition, H3K27Me3 inhibition in the skin, a marker of biologic activity, correlated to treatment exposure, with near maximal inhibition predicted by pharmacokinetic exposure at 800 mg.

Currently, a phase 2 dose of 800 mg BID is under consideration. A final recommendation for the phase 2 dose will be approved by a data monitoring committee based on efficacy, safety, and pharmacokinetic/pharmacodynamic parameters.

Lab mouse

Previous studies have shown that inhibiting the activity of the Malt1 protein can kill lymphoma cells.

Now, research published in Cell Reports has revealed that it also causes the immune system to malfunction.

Malt1 carries out a variety of tasks in lymphocytes, including acting as a protease that breaks down messenger substances and controls their quantity.

Until now, researchers were unsure about the role the protease function plays in immune cell development.

Several years ago, Jürgen Ruland, PhD, of Technische Universität München in Germany, and his colleagues turned their attention to this question.

Via cell culture experiments, the researchers found that blocking the protease function of Malt1 kills lymphoma cells. The team decided to test this strategy in an animal model to shed light on the exact function of Malt1 protease.

“It’s only possible to study complex interactions in the immune system, which comprises a finely orchestrated interplay of various cell types, in an intact organism, not in cell cultures,” Dr Ruland noted. “The processes are too complex to recreate in cells outside the body.”

The mice the researchers used were genetically modified so their Malt1 protein could no longer act as a protease but was still able to carry out all of its other functions.

The team was surprised to find that these mice developed severe signs of inflammation. Moreover, the immune system attacked and destroyed key neurons that coordinate movements.

The researchers were able to explain how this serious malfunction occurred and, in doing so, discovered an unexpected function of Malt1.

They found that, in the absence of the protease function, the mice were unable to produce regulatory T cells, and this caused their immune responses to spin

out of control.

The team also found that normal lymphocytes can be activated without the protease function of Malt1, but they release messenger substances uncontrollably, which causes inflammation.

“Our study showed that Malt1 protease is surprisingly important for the development of regulatory T cells and for damping the immune response in general,” Dr Ruland said. “Since the blockade of the protease function in the organism produces undesirable effects, new alternatives should urgently be sought for the treatment of lymphoma.”

Lab mouse

Previous studies have shown that inhibiting the activity of the Malt1 protein can kill lymphoma cells.

Now, research published in Cell Reports has revealed that it also causes the immune system to malfunction.

Malt1 carries out a variety of tasks in lymphocytes, including acting as a protease that breaks down messenger substances and controls their quantity.

Until now, researchers were unsure about the role the protease function plays in immune cell development.

Several years ago, Jürgen Ruland, PhD, of Technische Universität München in Germany, and his colleagues turned their attention to this question.

Via cell culture experiments, the researchers found that blocking the protease function of Malt1 kills lymphoma cells. The team decided to test this strategy in an animal model to shed light on the exact function of Malt1 protease.

“It’s only possible to study complex interactions in the immune system, which comprises a finely orchestrated interplay of various cell types, in an intact organism, not in cell cultures,” Dr Ruland noted. “The processes are too complex to recreate in cells outside the body.”

The mice the researchers used were genetically modified so their Malt1 protein could no longer act as a protease but was still able to carry out all of its other functions.

The team was surprised to find that these mice developed severe signs of inflammation. Moreover, the immune system attacked and destroyed key neurons that coordinate movements.

The researchers were able to explain how this serious malfunction occurred and, in doing so, discovered an unexpected function of Malt1.

They found that, in the absence of the protease function, the mice were unable to produce regulatory T cells, and this caused their immune responses to spin

out of control.

The team also found that normal lymphocytes can be activated without the protease function of Malt1, but they release messenger substances uncontrollably, which causes inflammation.

“Our study showed that Malt1 protease is surprisingly important for the development of regulatory T cells and for damping the immune response in general,” Dr Ruland said. “Since the blockade of the protease function in the organism produces undesirable effects, new alternatives should urgently be sought for the treatment of lymphoma.”

Lab mouse

Previous studies have shown that inhibiting the activity of the Malt1 protein can kill lymphoma cells.

Now, research published in Cell Reports has revealed that it also causes the immune system to malfunction.

Malt1 carries out a variety of tasks in lymphocytes, including acting as a protease that breaks down messenger substances and controls their quantity.

Until now, researchers were unsure about the role the protease function plays in immune cell development.

Several years ago, Jürgen Ruland, PhD, of Technische Universität München in Germany, and his colleagues turned their attention to this question.

Via cell culture experiments, the researchers found that blocking the protease function of Malt1 kills lymphoma cells. The team decided to test this strategy in an animal model to shed light on the exact function of Malt1 protease.

“It’s only possible to study complex interactions in the immune system, which comprises a finely orchestrated interplay of various cell types, in an intact organism, not in cell cultures,” Dr Ruland noted. “The processes are too complex to recreate in cells outside the body.”

The mice the researchers used were genetically modified so their Malt1 protein could no longer act as a protease but was still able to carry out all of its other functions.

The team was surprised to find that these mice developed severe signs of inflammation. Moreover, the immune system attacked and destroyed key neurons that coordinate movements.

The researchers were able to explain how this serious malfunction occurred and, in doing so, discovered an unexpected function of Malt1.

They found that, in the absence of the protease function, the mice were unable to produce regulatory T cells, and this caused their immune responses to spin

out of control.

The team also found that normal lymphocytes can be activated without the protease function of Malt1, but they release messenger substances uncontrollably, which causes inflammation.

“Our study showed that Malt1 protease is surprisingly important for the development of regulatory T cells and for damping the immune response in general,” Dr Ruland said. “Since the blockade of the protease function in the organism produces undesirable effects, new alternatives should urgently be sought for the treatment of lymphoma.”